Different types of cancer have been shown to involve at least in part over activation of receptor-tyrosine-kinases such as cMET, and VEGFR. Cancers include e.g. colorectal cancer, breast cancer, liver cancer and pancreatic cancer.
DB:SL
CD44 has been discussed as having a role in e.g. HGF and VEGF dependent activation of receptor-tyrosine-kinases such cMET, RON and VEGFR (see inter alia, Ponta et al., Nature Reviews (2003), 4, 33-45 and Tremmel et al., Blood (2009), 25, 5236-5244) which activate downstream MAP kinases like Erk. Further, expression of an alternatively spliced form of CD44, namely CD44v6 has been shown to occur in some of the cancers being characterized by over-activation of receptor-tyrosine-kinases. Peptides, which are able to block CD44v6 mediated activation of receptor-tyrosine-kinases have been discussed as being potentially useful in treatment of such cancers.
However, there is a continuing interest for pharmaceutically active agents that allow treatment of such cancers.
For example, treatment of pancreatic cancer typically depends on the stage of the cancer. Although only localized cancer is considered suitable for surgery with curative intent at present, only about 20% of cases are diagnosed with localized disease. Surgery can also be performed for palliation, if the malignancy is invading or compressing the duodenum or colon. Further treatment options include radiation and palliative chemotherapy. At present chemotherapy includes treatment with gemcitabine or combination therapies with gemcitabine such as gemcitabine/oxaliplatin or gemcitabine/cisplatin. Despite intensive research efforts, no treatment is currently available which would be considered to provide a long-term progression-free survival. Pancreatic cancer is therefore to date one of the malignancies with the worst prognosis of all neoplasias. Particularly if metastases have spread across the body such as to the liver, the peritoneal cavity and the lungs, no efficient treatment is available, which would allow to effectively regression of existing metastases.
Similar problems exist for other cancers, which have already formed metastases. For many of these cancers, palliative chemotherapy may be the only therapeutic option.
Angiogenesis denotes the formation of new blood vessels from already existing vessels. Although angiogenesis is in general a normal process in growth and development, it plays an essential role in malignant tumors since new blood vessels are required to provide the growing tumor with nutrients and oxygen. Tumors induce angiogenesis by secreting various growth factors, such as bFGF and VEGF which induce capillary growth into the tumor. Therefore, anti-angiogenesis reagents have gained increasing importance in cancer treatment.
Thus, there is a need for new compounds and methods which can be used to treat cancers such as pancreatic and liver cancers, before metastasis and when metastatic spreading has already occurred. It is further desirable that these compounds act as anti-angiogenesis agents to prevent the formation of new blood vessels which could provide the tumor with nutrients.